Process for the manufacture of delta-unsaturated 3-ketones of the sexual hormone series



Patented Jan. 28, 1941 PROCESS FOR. THE MANUFACTURE OF A -UNSATURATED 3-KETONES OF THE SEXUAL HORMONE SERIES Karl Miescher, Riehen, and Albert Wettstein,

Basel, Switzerland, assignors, by mesne assignments, to Ciba Pharmaceutical Products, Incorporated, Summit, N. J., a

Jersey corporation of New No Drawing. Application May 3, 1938," Serial No. 205,780. In Switzerland June 3, 1937 4 Claims. (Cl. 260-397) 5 contain in the nucleus A-B one of the atom groupings v o- 0= I Q\ L/ in which X stands for a free, esterified or etheri fled hydroxyl group. Among compounds of the sexual hormone series having the above named grouping there areto be understood compounds of the type of male or the like, for instance A -3:4:17:20:21-pentbut have at the carbon atom 17 of the ring D,

A may have carbonyl groups in the side chains. They may further be obtained for example by splitting off hydrogen halide from 3-oxy-5:6-dihalogen compounds. Others may be prepared by the addition in pairs of hydroxyl groups to the A or A unsaturated compounds, in which case hydroxyl groups may also be added to any existing double unions in the side chain As already mentioned above, the group X in the parent materials may also be an esterified or etheriiied hydroxyl group so that one may start for example from benzoic acid esters, palmitic acid esters, acetic acid esters and occasionally from xanthic acid esters or also from triarylmethyl ethers, phenolates and the like.

Finally, one may also start from other compounds of the sexual hormone series which under the working conditions of the elimination of HX can produce intermediately the above atom groupings, as is the case for example with 3,4,5-, 3,4,6 or 3,5,6-trioxy compounds.

The elimination of HX takes place with agents which, as is known, are suitable for such reactions (of. for example Houben "Die Arbeitsmethoden der organischen Chemie, 3rd edition, vol. 2, pages 947 et seq). The parent materials may be dehydrated for example by the action of mineral acids, frequently in alcohols or dioxane, of phosphorus-oxy-chloride, bisulfates, formic acid, oxalic acid or acid anhydrides, such as acetic acid anhydride, phosphorus pentoxide, by the action of catalysts, such as iodine, of raised temperature in indifferent gases or under diminished pressure. Also the elimination ofthe ester or ether radicals (carboxylic acids, alcohols, phenols) is often advantageously conducted thermally and in a vacuum. Moreover, the known suitable agents may be used for this elimination. In addition to the elimination of water or ester or ether groups in the rings A and B an analogous reaction may also happen at other points of the molecule, for instance hydroxyl groups may be eliminated in the form of water at C11 and C11. In special cases of a side chain androstendione -(3,17), androsteno1-(1'l)- one (-3) pregnendione- (3,20) 11,21-dioxy-pregnendior A -3-oxy-compounds which, if desired,

one-(3,20) 21-oiw-pregnendione-(330) or their derivatives. are therapeuticallyvaluable compounds or may be converted into such.

The following examples illustrate the invention, the parts being by weight:

- Example 1 CH: CH

The same compound is obtained in similar manner from M -androstentriol-(3,6,1?). Also by heating 3,5,6,17-tetroxy-androstane with potassium bisulphate in a vacuum A -androstenol- (1'7)-one-(3) is obtained.

Example 2 2 parts of a mixture of A--3,4-dioxy-androstenone-(17) and A --3,6-dioxy androste none (17), as obtained by the action of selenium dioxide on trans-dehydro-androsterone, are mixed with 100 parts of alcohol and 5 parts of sulphuric acid of 30% strength and the mixture is boiled under reflux for 20 minutes.

The whole is then poured into water, extracted with ether, the etherial solution washed with water, dried and evaporated in a vacuum. From the residue there may be obtained by direct recrystallisation or by the intermediate formation of a sparingly soluble disemicarbazone A -androstendione-(Zi, 1'7) of melting point 173-174 C. and of the formula on, on;

Ezamplet The benzoate obtained from 4-oxy-pregnandione-(3,20) of melting point 156-158 C. by the action of benzoylchloride in pyridine is heated in a high vacuum until almost the whole of the substance has sublimed. The colourless sublimate is dissolved in hexane and the solution is washed for separating benzoic acid by means of an aqueous solution of bicarbonate; it is then dried and evaporated, whereby there is obtained directly or by intermediate conversion into the Very sparingly soluble disemicarbazone A -pregnendione- (8.20) of the formula CH: CH;

3-0 0-OH: 0 V

This body recrystallises from hexane in dimor- Example 4 1 part of the mixture of A --3,4,17,20,21- pentoxy-pregnenes and A -3,6,17,20,2l-pentoxypregnenes which is obtainable by reaction of selenium dioxide on A --3,17-dioxy-21-oxo-pregnene and final reduction is mixed with 100 parts or alcohol and 6 parts of concentrated hydrochloric acid, and the mixture is heated for half an hour at 60" C. and then precipitated by addition of water; it is extracted with ether, the etherial solution is washed with bicarbonate solution and water and then dried and evaporated. From the residue fractional crystallisation from dilute methanol, if necessary after removal of the diketone fraction by means of a carbonyl reagent, for instance basically substituted acetic acid hydrazide, yields A -2l-hydroxy-pregnendione- (3,20) of the formula CH: CH:

which melts at, 139-141" C. and has a revival effect on rats from which the suprarenal capsules have been removed.

What we claim is:

1. A process for the manufacture of M' -unsaturated 3-ketones of the sexual hormoneseries, which comprises reacting a compound of this series containing in the nucleus A-B a grouping selected from the class consisting of no 3 5 no 0- wherein X stands for a member of the group consisting of a free and an esterified hydroxyl group, with a member of the group consisting of waterand acid-eliminating agents.

2. A' process for the manufacture of A -unsaturated 3-ketones of the sexual hormone series.

dehydrawhichcomprises react? a compound of this series containing in the ucleus i-B the group- 1 8 X wherein X stands for a member. of the group consisting of free hydroxyl and esterified hydroxyl, with a member of the group consisting of waterand acid-eliminating agents, whereby the said grouping is, in an intermediate stage, con- 1 verted into the grouping.

' wherein x has the significance hereinbefore set saturated 3-ketones oi the sexual hormone series, which comprises reacting a compound of this series containing in the nucleus AB the groupa B H0-L wherein X stands for a member of the group consisting of free hydroxyl and esterifled hydroxyl, with a member of the group consisting of waterand acid-eliminating agents, whereby the said grouping is, in an intermediate stage, converted into the grouping wherein x has the significance hereinbeiore set forth, and is then converted into the grouping 4. A process for the manufacture oi testosterone, comprising treating A--androstentrio1- (3,4,1?) with a water-eliminating agent.

KARL MIESCHER. I ALBERT WE'I'ISTEIN. 

